Singh Sindhu, Shi Qian, Bailey Shannon T, Palczewski Marek J, Pardee Arthur B, Iglehart J Dirk, Biswas Debajit K
Department of Cancer Biology, Dana-Farber Cancer Institute, Smith Room 1058, 44 Binney Street, Boston, MA 02115, USA.
Mol Cancer Ther. 2007 Jul;6(7):1973-82. doi: 10.1158/1535-7163.MCT-07-0063.
Nuclear factor-kappaB (NF-kappaB), a transcription factor with pleotropic effects, is a downstream mediator of growth signaling in estrogen receptor (ER)-negative and erbB family particularly erbB2 (HER-2/neu) receptor-positive cancer. We previously reported activation of NF-kappaB in ER-negative breast cancer cells and breast tumor specimens, but the consequence of inhibiting NF-kappaB activation in this subclass of breast cancer has not been shown. In this study, we investigated the role of NF-kappaB activation by studying the tumorigenic potential of cells expressing genetically manipulated, inducible, dominant-negative inhibitory kappaB kinase (IKK) beta in xenograft tumor model. Conditional inhibition of NF-kappaB activation by the inducible expression of dominant-negative IKKbeta simultaneously blocked cell proliferation, reinstated apoptosis, and dramatically blocked xenograft tumor formation. Secondly, the humanized anti-erbB2 antibody trastuzumab (Herceptin) and the specific IKK inhibitor NF-kappaB essential modifier-binding domain peptide both blocked NF-kappaB activation and cell proliferation and reinstated apoptosis in two ER-negative and erbB2-positive human breast cancer cell lines that are used as representative model systems. Combinations of these two target-specific inhibitors synergistically blocked cell proliferation at concentrations that were singly ineffective. Inhibition of NF-kappaB activation with two other low molecular weight compounds, PS1145 and PS341, which inhibited IKK activity and proteasome-mediated phosphorylated inhibitory kappaB protein degradation, respectively, blocked erbB2-mediated cell growth and reversed antiapoptotic machinery. These results implicate NF-kappaB activation in the tumorigenesis and progression of ER-negative breast cancer. It is postulated that this transcription factor and its activation cascade offer therapeutic targets for erbB2-positive and ER-negative breast cancer.
核因子-κB（NF-κB）是一种具有多效性的转录因子，是雌激素受体（ER）阴性且erbB家族尤其是erbB2（HER-2/neu）受体阳性癌症中生长信号的下游介质。我们之前报道过在ER阴性乳腺癌细胞和乳腺肿瘤标本中NF-κB的激活，但尚未显示抑制该亚类乳腺癌中NF-κB激活的后果。在本研究中，我们通过在异种移植肿瘤模型中研究表达基因操作的、可诱导的、显性负性抑制性κB激酶（IKK）β的细胞的致瘤潜力，来探讨NF-κB激活的作用。通过显性负性IKKβ的可诱导表达对NF-κB激活进行条件性抑制，同时阻断细胞增殖、恢复细胞凋亡，并显著阻断异种移植肿瘤的形成。其次，人源化抗erbB2抗体曲妥珠单抗（赫赛汀）和特异性IKK抑制剂NF-κB必需修饰因子结合域肽，在两个用作代表性模型系统的ER阴性且erbB2阳性的人乳腺癌细胞系中，均阻断了NF-κB激活和细胞增殖，并恢复了细胞凋亡。这两种靶向特异性抑制剂的组合在单独无效的浓度下协同阻断细胞增殖。用另外两种低分子量化合物PS1145和PS341抑制NF-κB激活，它们分别抑制IKK活性和蛋白酶体介导的磷酸化抑制性κB蛋白降解，阻断了erbB2介导的细胞生长并逆转了抗凋亡机制。这些结果表明NF-κB激活参与了ER阴性乳腺癌的肿瘤发生和进展。据推测，这种转录因子及其激活级联为erbB2阳性和ER阴性乳腺癌提供了治疗靶点。
